The Hidden Killers

Superfical mycoses

Subcutaneous mycoses

Systemic mycoses

Yeast vs. molds

WHO Fungal Priority Pathogens List (2022)

Evolution of Antifungal Development

Antifungal Targets

Antifungal targets

Antifungal Spectrum of Activity

Tissue Distribution Matters!

Invasive Candidiasis: Overview

• Most common invasive fungal infection in hospitalized patients
• Annual incidence: 2-14 per 100,000 persons
• Attributable mortality: 15-25%
• Hospital costs: $40,000-$70,000 per episode

Changing Epidemiology of Candida Species

Risk Factors for Invasive Candidiasis

Pathogenesis of Invasive Candidiasis

flowchart LR
    A[Colonization] --> B[Barrier Breach]
    B --> C[Local Invasion]
    C --> D[Bloodstream]
    D --> E[Dissemination]
    E --> F[End-Organ Disease]

• Candida are commensals of GI tract, skin, mucosa
• Invasion requires breakdown of defenses
• Biofilm formation on devices complicates treatment

Clinical Presentations

The “Missing 50%”

• Sensitivity of blood cultures: 21-71%
• Time to positivity: 2-5 days
• Many patients die before cultures turn positive
• Tissue infections may be blood culture-negative

Non-Culture Diagnostics

Treatment Algorithm for Candidemia

flowchart TD
    A[Candidemia] --> B{Hemodynamic Status}
    B -->|Unstable| C[Echinocandin]
    B -->|Stable| D{Prior Azole Exposure?}
    D -->|Yes| C
    D -->|No| E[Fluconazole Option]
    C --> F[Species ID + Susceptibility]
    E --> F
    F --> G[De-escalation if appropriate]

Source Control is Critical

Duration of Therapy

• Uncomplicated candidemia:
  • 14 days after first negative blood culture
  • AND resolution of signs/symptoms
• Metastatic complications:
  • Extended duration based on site
  • Endocarditis: 6+ weeks after valve surgery
  • Osteomyelitis: 6-12 months

Antifungal Susceptibility Testing

Candida auris: Emerging Threat

• First identified in Japan, 2009
• Multidrug resistance common
• Persists in environment
• Causes healthcare outbreaks
• Difficult to identify (often misidentified as other species)
• Associated with high mortality

Cryptococcosis: Global Impact

Cryptococcus Species

Clinical Manifestations

Elevated Intracranial Pressure

Mechanism:

• Capsular polysaccharide clogs arachnoid villi
• Impaired CSF reabsorption
• NOT usually communicating hydrocephalus

Diagnosis of Cryptococcosis

CSF Findings in Cryptococcal Meningitis

The AMBITION Trial

Regimen:

• Single dose L-AMB 10 mg/kg
• • Flucytosine 100 mg/kg/day × 14 days
• • Fluconazole 1200 mg/day × 14 days

Results:

• 10-week mortality: 24.8% vs 28.7%
• Fewer adverse events
• Simplified treatment

Treatment Phases

Prognosis Factors

Poor outcomes associated with:

• High CSF fungal burden
• Altered mental status at presentation
• Elevated opening pressure
• Low CSF white cell count
• Underlying malignancy
• Inadequate ICP management
• Delayed ART initiation (but too early also problematic)

Spectrum of Aspergillus Diseases

Aspergillus Species

Risk Factors for Invasive Aspergillosis

Bronchial-Alveolar Phase

Angioinvasive Phase: Progression

CT Findings: Halo Sign

Disease Patterns Depend on Immune Status

Galactomannan Testing

Diagnosis Summary

Culture and Histopathology:

• BAL culture: Sensitivity 50-60%
• Tissue biopsy: Septate hyphae, acute-angle (45°) branching
• PAS and GMS stains highlight fungal elements

Biomarkers:

• Galactomannan (serum and BAL)
• β-D-glucan (pan-fungal)
• Aspergillus PCR (emerging)

Treatment: First-Line Options

Treatment: Breakthrough Aspergillosis

Triazole Resistance: Emerging Threat

• TR34/L98H, TR46/Y121F/T289A mutations
• Environmental origin (agricultural fungicides)
• Prevalence varies geographically
• Associated with treatment failure
• Consider resistance testing in high-risk areas

Duration and Prognosis

Duration:

• Minimum 6-12 weeks
• Continue until resolution of lesions
• Continue until reversal of immunosuppression
• Consider secondary prophylaxis

Prognosis Depends On:

• Early diagnosis and treatment
• Neutrophil recovery
• Underlying disease control
• Site of infection
• Triazole resistance

Mucorales: The Scariest Fungi?

Ecology of Mucorales

Risk Factors for Mucormycosis

Common Mucorales Species

Pathogenesis

flowchart LR
    A[Spore Inhalation] --> B[Macrophage Engulfment]
    B -->|Impaired by steroids| C[Hyphal Growth]
    C --> D[Iron Acquisition]
    D -->|Promoted by DKA, acidosis| E[Angioinvasion]
    E --> F[Thrombosis & Necrosis]

MRI: “Black Turbinate Sign”

Pulmonary Mucormycosis

Diagnosis of Mucormycosis

Diagnostic Approach:

• Histopathology: Wide, ribbon-like, pauciseptate hyphae
• Culture: Rapid growth (“lid lifter”)
• PCR/sequencing: Available in specialized centers
• MALDI-TOF: For isolate identification

Antifungal Therapy

Initial:

• Liposomal amphotericin B 5-10 mg/kg/day
• Higher doses for CNS involvement
• May need prolonged IV therapy

Step-down:

• Posaconazole or isavuconazole
• For patients responding or with toxicity
• Can be used for consolidation/maintenance

Surgical Management

Amphotericin B: Nephrotoxicity Mechanism

• Afferent arteriole constriction → ↓ renal blood flow
• Tubuloglomerular feedback → further vasoconstriction
• LDL-bound AMB accumulates in tubules (LDL receptors)
• Direct tubular toxicity
• Electrolyte wasting (K⁺, Mg²⁺, Na⁺)

Liposomal AMB Reduces Nephrotoxicity

Mechanism:

• Liposomes don’t undergo glomerular filtration
• Reduced binding to tubular LDL receptors
• Less direct tubular damage

Triazole Toxicities Overview

Monitoring Recommendations

Key Take-Home Messages

Questions?

Case 1: Candidemia

Clinical Scenario:

55-year-old male, recent abdominal surgery, TPN, central line, develops fever on antibiotics.

Case 3: Suspected Invasive Aspergillosis

Clinical Scenario:

60-year-old female, AML induction, neutropenic day 18, persistent fever, new pulmonary nodules with halo sign.

EORTC/MSG Criteria: Proven IFI

Proven Invasive Fungal Infection:

• Histopathologic evidence of fungal elements from tissue specimen
• OR positive culture from normally sterile site
• OR blood culture positive for fungus (except Aspergillus)

Antifungal Drug Interactions

Key CYP450 Interactions:

Antifungal Dosing Reference